PCSK9 antibody preparations for delivery into a lumen of the intestinal tract using a swallowable drug delivery device

Abstract

Embodiments provide swallowable devices, preparations and methods for delivering therapeutic agents (TAs) within the GI tract such as antibodies (AP-antibodies) or other proteins which neutralize PCSK9 molecules. Many embodiments provide a swallowable device e.g., a capsule for delivering TAs into the intestinal wall (IW). Embodiments also provide TA preparations that are configured to be contained within the capsule, advanced from the capsule into the IW and/or peritoneum and degrade to release the TA into the bloodstream to produce a therapeutic effect. The preparation can be operably coupled to delivery means having a first configuration where the preparation is contained in the capsule and a second configuration where the preparation is advanced out of the capsule into the IW. Embodiments are particularly useful for delivery of AP-antibodies and related TA's for the treatment of cholesterol, lipid and related conditions where such TAs are poorly absorbed and/or degraded within the GI tract.

What is claimed is: 
     
       1. A therapeutic preparation comprising an anti-PCSK9 antibody (AP-antibody) in solid form, the preparation shaped as a solid tissue penetrating member configured to penetrate and be inserted into an intestinal wall or surrounding tissue after oral ingestion by application of force on the tissue penetrating member, wherein after insertion, the tissue penetrating member is retained within the intestinal wall or surrounding tissue and releases the AP-antibody into a blood stream from the intestinal wall or surrounding tissue, the preparation containing a dose of AP-antibody in a range from about 1 to 15 mg. 
     
     
       2. The preparation of  claim 1 , wherein the tissue penetrating member is structured as a shaft having a pointed end. 
     
     
       3. The preparation of  claim 2 , wherein the tissue penetrating member has a dart like or needle like structure. 
     
     
       4. The preparation of  claim 1 , wherein the force is a mechanical force. 
     
     
       5. The preparation of  claim 1 , wherein the AP-antibody is released into the blood stream from the intestinal wall or surrounding tissue to achieve a Cmax in a shorter time period than a time period to achieve the Cmax for an extravascularly injected dose of the AP-antibody. 
     
     
       6. The preparation of  claim 5 , wherein the tmax for the AP-antibody released from the tissue penetrating member is about 50% of the tmax for the extravascularly injected dos of AP-antibody. 
     
     
       7. The preparation of  claim 5 , wherein the tmax for the AP-antibody released from the tissue penetrating member is about 30% of the tmax for the extravascularly injected dose of AP-antibody. 
     
     
       8. The preparation of  claim 5 , wherein the tmax for the AP-antibody released from the tissue penetrating member is about 10% of the tmax for the extravascularly injected dose of AP-antibody. 
     
     
       9. The preparation of  claim 5 , wherein the extravascular injection is a subcutaneous injection or an intramuscular injection. 
     
     
       10. The preparation of  claim 1 , wherein the preparation is adapted for insertion into the wall of the small intestine. 
     
     
       11. The preparation of  claim 1 , wherein the preparation is adapted to be orally delivered in a swallowable capsule. 
     
     
       12. The preparation of  claim 11 , wherein the preparation is adapted to be operably coupled to delivery means having a first configuration and a second configuration, the preparation being contained within the capsule in the first configuration and advanced out of the capsule and into the intestinal wall or surrounding tissue in the second configuration. 
     
     
       13. The preparation of  claim 12 , wherein the delivery means comprises at least one expandable balloon having an expanded and a non-expanded state and the first configuration is the non-expanded state and the second configuration is the expanded state. 
     
     
       14. The preparation of  claim 1 , wherein the preparation comprises a biodegradable material which degrades within the intestinal wall or surrounding tissue to release AP-antibody into the blood stream. 
     
     
       15. The preparation of  claim 1 , wherein the biodegradable material comprises PGLA, polyethylene oxide, a sugar, or maltose. 
     
     
       16. The preparation of  claim 1 , wherein the preparation comprises at least one pharmaceutical excipient. 
     
     
       17. The preparation of  claim 16 , wherein at least one pharmaceutical excipient comprises at least one of a binder, a preservative or a disintegrant. 
     
     
       18. The preparation of  claim 17 , wherein the binder comprises PEG. 
     
     
       19. The preparation of  claim 1 , wherein the tissue penetrating member comprises a biodegradable material which degrades within the intestinal wall or surrounding tissue to release AP-antibody into the blood stream. 
     
     
       20. The preparation of  claim 19 , wherein the biodegradable material comprises maltose or PGLA or polyethylene oxide. 
     
     
       21. The preparation of  claim 1  wherein a weight percent of AP-antibody in the tissue penetrating member is between about 8 to 12%. 
     
     
       22. The preparation of  claim 1 , wherein the tissue penetrating member includes a retaining feature for retaining the tissue penetrating member within the intestinal wall or surrounding tissue after insertion. 
     
     
       23. The preparation of  claim 1 , wherein the AP-antibody is contained in the tissue penetrating member in a shaped section. 
     
     
       24. The preparation of  claim 23 , wherein the shaped section has a cylinder or pellet shape. 
     
     
       25. The preparation of  claim 1 , wherein a Cmax achieved by delivering the preparation by insertion into the intestinal wall or surrounding tissue is substantially greater than a Cmax achieved when the preparation is delivered orally without insertion into the intestinal wall or surrounding tissue. 
     
     
       26. The preparation of  claim 25 , wherein the Cmax achieved by delivering the preparation by insertion into the intestinal wall or surrounding tissue is at least about 100 greater than the Cmax achieved when the preparation is delivered orally without insertion into the intestinal wall or surrounding tissue. 
     
     
       27. The preparation of  claim 1 , wherein the preparation is configured to produce a long-term release of AP-antibody. 
     
     
       28. The preparation of  claim 27 , wherein the preparation is configured to produce the long-term release of AP-antibody to produce a selectable t ½. 
     
     
       29. The preparation of  claim 28 , wherein the t ½ is about 40 days. 
     
     
       30. The preparation of  claim 1 , wherein the AP-antibody is selected from the group consisting of Alirocumab, Evolocumab, and Bococizumab. 
     
     
       31. The preparation of  claim 30 , wherein when inserted into the intestinal wall or surrounding tissue of a patient on a daily basis, the preparation results in a percent steady state fluctuation in plasma concentration of AP-antibody in the patient in a range of about 0.12 to about 0.39%. 
     
     
       32. The preparation of  claim 1 , wherein the preparation contains a dose of AP-antibody in a range from about 2 to 10 mg. 
     
     
       33. A therapeutic preparation comprising an anti-PCSK9 antibody (AP-antibody) in solid form, the preparation adapted for insertion and retention in an intestinal wall or surrounding tissue after oral ingestion by application for force on the preparation, wherein upon insertion, the preparation is degraded by fluids within the intestinal wall or surrounding tissue to release the AP-antibody into the bloodstream from the intestinal wall or surrounding tissue to achieve a t ½ that is greater than the t ½ for orally ingested AP-antibody that is not inserted into the intestinal wall, the preparation containing a dose of AP-antibody in a range from about 1 to 15 mg. 
     
     
       34. The preparation of  claim 33 , wherein the t ½ of the AP-antibody inserted into the intestinal wall or surrounding tissue is at least about 10 times greater than the t ½ for the orally ingested AP-antibody that is not inserted into the intestinal wall or surrounding tissue. 
     
     
       35. The preparation of  claim 33 , wherein the AP-antibody is selected from the group consisting of Alirocumab, Evolocumab, and Bococizumab. 
     
     
       36. The preparation of  claim 33 , wherein the force is a mechanical force.